Use of Amisulpride as an Anti-Emetic

ABSTRACT

Amisulpride is used in the therapy of nausea, vomiting or retches. The therapy may utilize a novel injectable formulation, in unit dosage form, comprising less than 50 mg amisulpride.

FIELD OF THE INVENTION

This invention relates to the use of amisulpride in the therapy ofnausea, vomiting and retching.

BACKGROUND OF THE INVENTION

Emesis is the act of vomiting and can be described as the forcefulexpulsion of gastrointestinal contents through the mouth brought aboutby the descent of the diaphragm and powerful contractions of theabdominal muscles. Emesis is usually, but not always, preceded bynausea. Retching (or dry heaves) involves the same physiologicalmechanisms as vomiting, but occurs against a closed glottis. Nausea maybe defined as a desire to vomit but which is not associated withexpulsive muscular movement.

Vomiting, nausea, retching or any combination (hereinafter referred toas “the symptoms”) can be caused by a number of factors includinganaesthetics, radiation, cancer chemotherapeutic agents, toxic agents,medicines, for example serotonin reuptake inhibitors, analgesics such asmorphine, antibiotics, pregnancy and motion. Conditions which areassociated with vertigo, for example Meniere's disease, can also causethe symptoms. Headache, caused by for example migraine, increasedintracranial pressure or cerebral vascular haemorrhage can also resultin the symptoms. Other maladies associated with the symptoms includecholecystitis, choledocholithiasis, intestinal obstruction, acutegastroenteritis, perforated viscus, dyspepsia resulting from, forexample, gastroesophogeal reflux disease, peptic ulcer disease,gastroparesis, gastric or oesophageal neoplasms, infiltrive gastricdisorders (e.g. Menetrier's syndrome, Crohn's disease, eosinophilicgastroenteritis, sarcoidosis and amyloidosis), gastric infections,parasites, chronic gastric volvulus, chronic intestinal ischaemia,altered gastric motility disorders and/or food intolerance orZollinger-Ellson syndrome. In some cases of the symptoms, no etiologycan be determined, as for example in Cyclic Vomiting Syndrome.

The symptoms may be defined as acute when they are present for less thana week. The causes of the symptoms of short duration can be separablefrom etiologies leading to more chronic symptoms. The symptoms may bedefined as chronic when they are present for over a week; these can becontinuous or intermittent, and last for months or years.

Two areas of particular clinical relevance are nausea and vomitingresulting from surgical procedures (post-operative nausea and vomiting,or PONV) or chemotherapeutic agents and radiation therapy(chemotherapy-induced nausea and vomiting, or CINV). The symptoms causedby chemotherapeutic agents can be so severe that the patient refusesfurther treatment. Three types of emesis are associated with the use ofchemotherapeutic agents, i.e. acute emesis, delayed emesis andanticipatory emesis.

PONV is a significant issue for patients and healthcare providers. It israted second only to pain as the complication most feared by patients,and contributes significantly to anxiety and patient distress. Vomitingcan have an adverse impact on surgical wound sites, especially upper GItract surgery.

Risk factors for PONV include type of surgery, gender (women are moreprone than men to PONV), smoking history, prior history of PONV ormotion sickness, length of surgery, use of volatile anaesthetics andopioid analgesic usage. Certain operations seem to be particularlyassociated with PONV, including procedures on the eyes and ears,laparoscopic cholecystectomy and hysterectomy, breast surgery and majorabdominal and gynaecological surgery.

PONV is typically treated using a dopamine D2 antagonist such asdroperidol. This drug was given a black box warning by the FDA in 2001on the basis of cardiotoxicity, believed to be related to a propensityof the drug to block HERG channels and cause QT prolongation.

Amisulpride, an atypical antipsychotic D2 antagonist, has beneficialactions in schizophrenic patients. For patients characterised bypredominant negative symptoms, oral doses of 50-300 mg/day arerecommended. It is reported in the UKPAR (Special Warnings andPrecautions for Use) that amisulpride induces a dose dependentprolongation of the QT interval.

Amisulpride is marketed as Solian, a solution for intramuscularadministration, comprising water, hydrochloric acid, sodium chloride andamisulpride. An ampoule contains amisulpride at 200 mg/4 ml solution.

U.S. Pat. No. 4,294,828 discloses amisulpride and related compoundshaving anti-apomorphine and anti-serotonin activity. Amisulpride isreported to inhibit apomorphine-induced vomiting in the dog, therebyconfirming that amisulpride is a functional D2 antagonist. It issuggested that the compounds should be administered at doses of 50-750mg/day, e.g. 200 mg/day.

SUMMARY OF THE INVENTION

The present invention relates to the use in man of amisulpride for thetherapy (including treatment and prophylaxis or preventative therapy) ofnausea, vomiting or retching. The condition may have any cause, e.g.motion sickness, but amisulpride may be particularly useful in therapyof PONV or in patients receiving cancer chemotherapy or radiotherapy.

As will be evident from the data presented below, amisulpride iseffective as an anti-emetic agent, even when the subject is receivingmorphine or cisplatin, both agents whose emetic effect is strong anddifficult to alleviate. Surprisingly, it is also effective at a dosewell below any that has previously been proposed for this drug.Therefore, although side-effects are not as much of a concern when usingamisulpride as in the case of some other anti-emetic drugs, such effectscan be minimised or avoided.

Another aspect of the invention is a product comprising amisulpride andan emetogenic agent, as a combined preparation for separate,simultaneous or sequential use in the therapy of a condition as definedherein.

A further aspect of the present invention is a buffered compositionsuitable for injection. Yet another aspect of the present invention is aunit dosage for injection comprising less than 50 mg amisulpride.

DESCRIPTION OF THE INVENTION

Amisulpride has a single chiral centre and 2 enantiomers exist, i.e.(S-)-amisulpride and (R+)-amisulpride. Substantially pure enantiomer ornon-racemic mixtures may be used, but it may be preferred to useracemate or (S-)-amisulpride.

For the purpose of the present invention, amisulpride may beadministered at dosages which are not associated with adversecardiovascular events. It is preferably administered by the intravenous,intramuscular, subcutaneous or oral route for the treatment of PONV,whilst for the treatment of CINV additional routes include sublingual,rectal, intranasal, topically applied directly to the skin, buccal orpulmonary inhaled.

A typical dosage, e.g. for intravenous administration, is from 1 to 48mg, e.g. up to 40 mg, preferably 1 to 35 mg or, depending on thecircumstances, 5 to 35 mg. Human doses of 2.5 to 20 mg may be effective.The drug may be given once, twice or more often each day, particularlyfor CINV. A single dosage may be sufficient for PONV. It will beunderstood, however, that the specific dose level for any particularpatient will depend upon a variety of factors including the age, bodyweight, general health, sex, diet, time of administration, drugcombination and the severity of the particular condition undergoingtherapy.

For intravenous injection, the amisulpride may be in the form of a salt,hydrate or solvate. Salts include pharmaceutically acceptable salts, forexample acid addition salts derived from inorganic or organic acids,such as hydrochlorides, hydrobromides, p-toluenesulphonates, phosphates,sulphates, perchlorates, acetates, trifluoroacetates, propionates,citrates, malonates, succinates, lactates, oxalates, tartrates andbenzoates.

Salts may also be formed with bases. Such salts include salts derivedfrom inorganic or organic bases, for example alkali metal salts such asmagnesium or calcium salts, and organic amine salts such as morpholine,piperidine, dimethylamine or diethylamine salts.

A pharmaceutical composition containing the active ingredient may be inany suitable form, for example aqueous or non-aqueous solutions orsuspensions, dispersible powders or granules, transdermal ortransmucosal patches, creams, ointments or emulsions.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or non-aqueous (e.g. oleaginous) solution orsuspension. The sterile injectable preparation may also be in a sterileinjectable solution or suspension in a non-toxic parenterally-acceptablediluent or solvent, for example as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,phosphate buffer solution, Ringer's solution and isotonic sodiumchloride solution. In addition, sterile, fixed oils are conventionallyemployed as a solvent or suspending medium. For this purpose, any blandfixed oil may be employed, including synthetic mono- or diglycerides. Inaddition, fatty acids such as oleic acid find use in the preparation ofinjectables. Suspensions may be formulated according to the known artusing those suitable dispersing or wetting agents and suspending agentswhich have been mentioned elsewhere.

Aqueous suspensions contain the active ingredient in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents such as a naturally occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such a polyoxyethylene with partial esters derived from fattyacids and hexitol anhydrides, for example polyoxyethylene sorbitanmonooleate. The aqueous suspensions may also contain one or morepreservatives, for example ethyl or n-propyl p-hydroxybenzoate, one ormore colouring agents, one or more flavouring agents, and one or moresweetening agents, such as sucrose or saccharin.

Non-aqueous (i.e. oily) suspensions may be formulated by suspending theactive ingredient in a vegetable oil, for example arachis oil, oliveoil, sesame oil or coconut oil, or in a mineral oil such as liquidparaffin. The oily suspensions may contain a thickening agent, forexample beeswax, hard paraffin or cetyl alcohol. These compositions maybe preserved by the addition of an anti-oxidant such as ascorbic acid.

Compositions for injection are typically aqueous, and comprise a buffer,e.g. citrate buffer. No other ingredients may be required. The pH ofsuch a composition may be, for example from 4 to 7, e.g. 5.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are known.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally occurring gums, for example gum acacia or gum tragacanth,naturally occurring phosphatides, for example soya bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monooleate.

The active agent may also be administered in the form of suppositoriesfor rectal administration of the drug. These compositions can beprepared by mixing the drug with a suitable non-irritating excipientwhich is solid at ordinary temperatures but liquid at the rectaltemperature and will therefore melt in the rectum to release the drug.Such materials are cocoa butter and polyethylene glycols.

For topical delivery, transdermal and transmucosal patches, creams,ointments, jellies, solutions or suspensions may be employed. Forsub-lingual delivery, fast dissolving tablet formulations may be used,as well as a number of the presentations described above. For oraladministration, amisulpride may be administered as tablets, capsules orliquids.

It may be advantageous to co-administer amisulpride with other classesof drug which can add additional benefits of efficacy and/or, bytitrating dosages downwards, result in fewer side-effects. Theseinclude, but are not limited to, antihistamines, 5-HT3 antagonistsincluding granisetron, ondansetron, palonosetron, dolasetron, andtropisetron, dexamethasone, aprepitant and other neurokinin-1 receptorantagonists and drugs such as nabilone.

It may also be advantageous to co-administer amisulpride with drugswhich are associated with emesis in man, for example certain opioidsincluding morphine. Amisulpride, at an appropriate concentrationdetermined by one of skill, can be formulated with the drug in question,for example morphine, in a dosing system such as an infusion bag orother appropriate dosage form.

By way of example, amisulpride and an emetogenic agent may beadministered to a subject in combination, simultaneously orsequentially. For example, amisulpride is given before treatment with,say, morphine or a chemotherapeutic agent such as cisplatin. Asindicated above, the route of administration may depend on the conditionbeing treated.

As indicated above, there are various causes of emesis. Examples ofconditions that may be treated by the use of amisulpride includeanaesthetics, radiation, cancer chemotherapeutic agents, toxic agents,medicines, for example serotonin reuptake inhibitors, analgesics such asmorphine, antibiotics, pregnancy, motion, conditions which areassociated with vertigo, for example Meniere's disease, headache, causedby for example migraine, increased intracranial pressure or cerebralvascular haemorrhage, cholecystitis, choledocholithiasis, intestinalobstruction, acute gastroenteritis, perforated viscus, dyspepsiaresulting from, for example, gastroesophogeal reflux disease, pepticulcer disease, gastroparesis, gastric or oesophageal neoplasms,infiltrive gastric disorders (e.g. Menetrier's syndrome, Crohn'sdisease, eosinophilic gastroenteritis, sarcoidosis and amyloidosis),gastric infections, parasites, chronic gastric volvulus, chronicintestinal ischaemia, altered gastric motility disorders and/or foodintolerance and Zollinger-Ellson syndrome.

The following studies provide evidence on which the invention is based.The preclinical evidence for efficacy against vomiting in PONV and CINVinvolves studies in ferrets, whilst efficacy against nausea can bedemonstrated in patients receiving a general anaesthetic procedure.

Study 1

Amisulpride, white powder, was dissolved in dimethylsulfoxide and thendiluted in physiological saline.

For vehicle control, physiological saline was used for s,c,administration (apomorphine experiments) and 8.3% DMSO in physiologicalsaline was used for i.v. administration (morphine, cisplatin).

Droperidol was dissolved in DMSO then diluted in lactic acid inphysiological saline, to a final DMSO concentration of 7.5%.

Apomorphine hydrochloride hemihydrates, white powder, was dissolved inphysiological saline.

Morphine hydrochloride, white powder, was dissolved in physiologicalsaline.

Cisplatinum II diamine dichloride, yellow powder, was dispersed in 0.2%hydroxymethylcellulose in physiological saline.

The method used to test antiemetic activity preclinically follows thatdescribed by Gardner et al . (Brit. J. Pharmacol., 116: 3158-3163, 1995)and uses ferrets.

Sixty minutes before administration of the test substance, ferrets areplaced in individual stainless steel cages (40×50×34 cm) with a gridfloor. Then, the animals are challenged with apomorphine (0.25 mg/kgs.c.), morphine (0.4 mg/kg i.p.) or cisplatin (10 mg/kg i.p.) andimmediately observed over at least a 2-hour period. Parameters recordedinclude: number of ferrets showing retches and vomits; latency to firstretching; latency to first vomiting; number of retches; vomiting (numberof vomits); number of emesis periods and mean duration of emesisperiods. Retching is defined as a rhythmic respiratory movement againsta closed glottis, while vomiting is defined as a forced expulsion ofupper gastrointestinal contents.

Where apomorphine is used as the emetogen, amisulpride (or vehicle) wasadministered subcutaneously (s.c. 30 minutes before administration ofapomorphine). Animals (6 per group) were treated with vehicle oramisulpride at 1, 10, or 100 μg/kg given sub-cutaneously. Theobservation period was 2 hours after apomorphine administration.

Where morphine is used as the emetogen, amisulpride (n=6 per group) orvehicle (n=6) is administered intravenously 5 minutes before theadministration of morphine. The observation period is 2 hours afteradministration of the morphine.

Where cisplatin is used as the emetogen, amisulpride (n=6 per group) orvehicle (n=6) is administered intravenously at least 5 minutes beforethe administration of cisplatin. The observation period is up to 72hours, which allows effects on early and late phase emesis to beobserved.

Apomorphine in the vehicle control group induced emesis in the ferretsover the 2 hour observation period (14.8±4.8 retches, 1.0±0.5 vomits,3.3±0.9 emesis periods). Retches and vomits occurred 319±53 and 621±308seconds after administration respectively. Amisulpride given at 1 μg/kg,30 minutes before apomorphine, decreased the emetic effects ofapomorphine as compared with the vehicle control group (6.0±2.2 retches,0±0 vomits and 1.5±0.6 emesis periods). Amisulpride at 10 and 100 μg/kgtotally inhibited the apomorphine emesis. This demonstrates that, asmight be expected, amisulpride blocks dopamine D2 receptors.

Morphine in the vehicle control group induces emesis in the ferrets overthe 2 hour observation period. Amisulpride reduces the emetic effectsinduced by morphine, in dose-dependent manner, as compared with thevehicle control group. The ED50 for amisulpride against morphine emesisis calculated. These data indicate that amisulpride has efficacy againstmorphine-induced emesis and that is effective when administered via theintravenous route.

More specifically, morphine in the control group induced the occurrenceof retches and vomits in 6 (retches) and 4 (vomits) of 6 animals, themean (±s.e.m.) values were 33.8±4.7 retches, 1.8±0.7 vomits and 7.5±1.5emesis periods. Retches and vomits occurred after 213±24 and 374±64seconds respectively. Amisulpride was given at 3, 6 and 12 mg/kg beforemorphine. Amisulpride at 3 mg/kg produced small decreases in retches to28.7±7.1 and emesis periods to 5.2±1.4 and abolished the incidence ofvomits. Amisulpride given at 6 mg/kg decreased the incidence of all 3parameters, retches to 17.8±6.8 (approximately a 50% decrease), vomitsto 0.5±0.3 (a 72% decrease) and emesis periods to 3.3±1.1 (a 56%decrease). The data from the first 2 dose levels demonstrate a doserelated reduction in emesis with amisulpride. Amisulpride given at 12mg/kg had no effect on retches 31.7±11.2, but still produced a reductionin vomits to 0.8±0.4 and slight reduction in emesis periods to 5.7±1.5.

These data demonstrate that amisulpride blocks morphine-induced emesis,and also that the drug may be less effective at higher dosages. It isreasonable to deduce that a dose of less than 50 mg will be effective ina human subject.

Cisplatin in the vehicle control group induces emesis over the 72 hourperiod. Amisulpride reduces the emetic effects of cisplatin, indose-dependent manner, as compared with the vehicle control group,having an effect on both early and late stages.

More specifically, data are reported from an experiment in which theobservation period was 3 hours following cisplatin challenge. Cisplatininduced the occurrence of retches and vomits in 7 and 5 of 9 animalstested respectively. The mean incidences were 79.8±22.2 retches, 3.0±1.1vomits and 10.7±2.8 emetic periods. Retches and vomits occurred after 85minutes 6 seconds±7 minutes 53 seconds and 86 minutes 39 seconds±10minutes 28 seconds respectively amisulpride was given at 0.2, 0.6, 2 and6 mg/kg. At 0.2 mg/kg the incidence of retches was 23.3±10.8 (a 71%decrease in mean value), of vomits 0.2±0.2 (a 93% decrease) and emesisperiods 3.7±2.0 (a 65% decrease). At 0.6 mg/kg the incidence of retcheswas 62.5±59.0, vomits 1.3±1.1 and emesis periods 3.7±1.3. It was notedin this group that one animal had an early, exaggerated response tocisplatin. At 2.0 mg/kg the incidence of retches was 3.3±2.5, vomits0.2±0.2 and emesis periods 0.5±0.3. It is clear that amisulpride at 0.6mg/kg (with one animal excluded), and 2 mg/kg is better than droperidolat 3 mg/kg. At 6 mg/kg the incidences were 11.7±3.8 retches, 1.2±1.0vomits and 3.7±1.3 emesis periods.

These data demonstrate that amisulpride blocks cisplatin-induced emesis,and also indicate that the drug may be less effective at higher dosages.Again, it is reasonable to deduce that a dose of less than 50 mg will beeffective in a human subject.

As indicated above, droperidol is a known agent for the treatment ofPONV. In a comparative experiment, droperidol was given 5 minutes beforecisplatin (using the methods described above) in 3 animals and it wasfound that, based on the incidence of nausea and vomiting, amisulprideat 0.6 mg/kg (with one animal which had the exaggerated responseexcluded) and 2 mg/kg is more effective than droperidol at 3 mg/kg.

Study 2

A formulation of the invention was prepared, suitable for intravenousadministration. It is a 2.5 mg/ml citrate-buffered solution (nominal pH5.0) of amisulpride. The composition is given below.

Quantity (g) per vial Component % w/v (10 mL fill) Amisulpride 0.25 0.025  Citric acid monohydrate 0.935 0.0935 Trisodium citrate 1.6320.1632 dihydrate Sodium chloride 0.18  0.018  Hydrochloric acid diluteqs qs Sodium hydroxide qs qs Water for injection To 100 To 10 mL

The effects of amisulpride are studied in patients undergoing routinesurgery in a randomised, controlled, open-label phase IIa study ofefficacy of a single dose as prophylaxis of post-operative nausea andvomiting. The primary endpoint is the incidence of nausea and vomitingin the 24-hour period post-operation. The drug is administered at thetime of the operation. The secondary endpoints are the nausea andvomiting rates and severity (measured separately) over 0-2 hours, 2-6hours and 6-24 hours post-operation. In addition, the use of rescuemedication and safety/adverse events are recorded. The data demonstratethe effect of amisulpride against the nausea as well as the vomiting andretching associated with PONV.

1. A method for the prevention and/or treatment of post-operative nauseaand vomiting wherein said method comprises administering, to a subjectin need of such prevention and/or treatment, amisulpride.
 2. The method,according to claim 1, wherein the subject is also administered anemetogenic agent.
 3. The method, according to claim 2, wherein thesubject has cancer and the emetogenic agent is a chemotherapeutic agent.4. The method, according to claim 2, wherein the emetogenic agent iscisplatin.
 5. The method, according to claim 2, wherein the emetogenicagent is an opiate.
 6. The method, according to claim 2, wherein theemetogenic agent is morphine.
 7. The method, according to claim 1,wherein the amisulpride is administered by intravenous injection.
 8. Themethod, according to claim 1, wherein the amisulpride is administered byintramuscular injection.
 9. The method, according to claim 1, whereinthe amisulpride is administered by subcutaneous injection.
 10. Themethod, according to claim 1, wherein the subject is a human.
 11. Themethod, according to claim 1, wherein the amisulpride is in the form ofa unit dose comprising less than 50 mg amisulpride.
 12. The method,according to claim 11, wherein the unit dose comprises 1 to 35 mgamisulpride.
 13. The method, according to claim 1, wherein theamisulpride is in the form of an acceptable pharmaceutical salt.
 14. Themethod, according to claim 1, wherein the amisulpride is administered incombination with another anti-emetic drug.
 15. The method, according toclaim 14, wherein the another anti-emetic drug is a 5HT3 antagonist. 16.The method, according to claim 15, wherein the 5HT3 antagonist isondansetron. 17-20. (canceled)